# Embed-Search-Align: DNA Sequence Alignment using Transformer Models

arXiv: https://arxiv.org/abs/2309.11087 · HTML: https://mlsanity.com/paper/2309.11087/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 26 of its 71 references that are in the map.
- First posted on arXiv 20 Sep 2023.

## Builds on (most cited first, 26 of 26)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [BERT: Pre-training of Deep Bidirectional Transformers for Language Understanding](https://mlsanity.com/paper/1810.04805/) (2018)
- [Language Models are Few-Shot Learners](https://mlsanity.com/paper/2005.14165/) (2020)
- [An Image is Worth 16x16 Words: Transformers for Image Recognition at Scale](https://mlsanity.com/paper/2010.11929/) (2020)
- [LLaMA: Open and Efficient Foundation Language Models](https://mlsanity.com/paper/2302.13971/) (2023)
- [A Simple Framework for Contrastive Learning of Visual Representations](https://mlsanity.com/paper/2002.05709/) (2020)
- [Retrieval-Augmented Generation for Knowledge-Intensive NLP Tasks](https://mlsanity.com/paper/2005.11401/) (2020)
- [Sentence-BERT: Sentence Embeddings using Siamese BERT-Networks](https://mlsanity.com/paper/1908.10084/) (2019)
- [On the Opportunities and Risks of Foundation Models](https://mlsanity.com/paper/2108.07258/) (2021)
- [wav2vec 2.0: A Framework for Self-Supervised Learning of Speech Representations](https://mlsanity.com/paper/2006.11477/) (2020)
- [Longformer: The Long-Document Transformer](https://mlsanity.com/paper/2004.05150/) (2020)
- [UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction](https://mlsanity.com/paper/1802.03426/) (2018)
- [Billion-scale similarity search with GPUs](https://mlsanity.com/paper/1702.08734/) (2017)
- [SimCSE: Simple Contrastive Learning of Sentence Embeddings](https://mlsanity.com/paper/2104.08821/) (2021)
- [Reformer: The Efficient Transformer](https://mlsanity.com/paper/2001.04451/) (2020)
- [BERT Rediscovers the Classical NLP Pipeline](https://mlsanity.com/paper/1905.05950/) (2019)
- [Efficient and robust approximate nearest neighbor search using Hierarchical Navigable Small World graphs](https://mlsanity.com/paper/1603.09320/) (2016)
- [MTEB: Massive Text Embedding Benchmark](https://mlsanity.com/paper/2210.07316/) (2022)
- [Pre-trained Models for Natural Language Processing: A Survey](https://mlsanity.com/paper/2003.08271/) (2020)
- [Check Your Facts and Try Again: Improving Large Language Models with External Knowledge and Automated Feedback](https://mlsanity.com/paper/2302.12813/) (2023)
- [Promptagator: Few-shot Dense Retrieval From 8 Examples](https://mlsanity.com/paper/2209.11755/) (2022)
- [HyenaDNA: Long-Range Genomic Sequence Modeling at Single Nucleotide Resolution](https://mlsanity.com/paper/2306.15794/) (2023)
- [DNABERT-2: Efficient Foundation Model and Benchmark For Multi-Species Genome](https://mlsanity.com/paper/2306.15006/) (2023)
- [BrainBERT: Self-supervised representation learning for intracranial recordings](https://mlsanity.com/paper/2302.14367/) (2023)
- [Audio Transformers](https://mlsanity.com/paper/2105.00335/) (2021)
- [Efficient Architecture-Aware Acceleration of BWA-MEM for Multicore Systems](https://mlsanity.com/paper/1907.12931/) (2019)

## Abstract (arXiv)

DNA sequence alignment involves assigning short DNA reads to the most probable locations on an extensive reference genome. This process is crucial for various genomic analyses, including variant calling, transcriptomics, and epigenomics. Conventional methods, refined over decades, tackle this challenge in 2 steps: genome indexing followed by efficient search to locate likely positions for given reads. Building on the success of Large Language Models in encoding text into embeddings, where the distance metric captures semantic similarity, recent efforts have explored whether the same Transformer architecture can produce embeddings for DNA sequences. Such models have shown early promise in classifying short DNA sequences, such as detecting coding/non-coding regions, and enhancer, promoter sequences. However, performance at sequence classification tasks does not translate to sequence alignment, where it is necessary to search across the genome to align each read, a significantly longer-range task. We bridge this gap by framing the Sequence Alignment task for Transformer models as an "Embed-Search-Align" task. In this framework, a novel Reference-Free DNA Embedding model generates embeddings of reads and reference fragments, which are projected into a shared vector space where the read-fragment distance is used as a surrogate for alignment. Technical contributions include: (1) Contrastive loss for self-supervised training of DNA sequence representations, facilitating rich reference-free, sequence-level embeddings, and (2) a DNA vector store to enable search across fragments on a global scale. DNA-ESA is 99% accurate when aligning 250-length reads onto a human genome (3gb), rivaling conventional methods such as Bowtie and BWA-Mem. DNA-ESA exceeds the performance of 6 Transformer model baselines such as Nucleotide Transformer, Hyena-DNA, and shows task transfer across chromosomes and species.